The Role of Recycling Immune Complexes in the Breakdown of Tolerance

回收免疫复合物在耐受性破坏中的作用

• 批准号: 8489788
• 负责人: BARBARA J VILEN
• 金额: $ 26.42万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8489788
• 关键词: Amyloid; Antigen-Antibody Complex; Antinuclear Antibodies; Apoptotic; Attenuated; Autoantibodies; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Binding; Blood Circulation; Bone Marrow; Bulla; Cell Death; Cell surface; Cells; Chronic; Clinical Trials; Complement 1q; Coupled; Cytokine Signaling; Data; Defect; Degradation Pathway; Dendritic Cells; Deoxyribonucleases; Deposition; Diffusion; Disease; EGF gene; Electron Microscopy; Endocytosis; Endosomes; Event; Failure; Fatty acid glycerol esters; Flow Cytometry; Fluorescence Microscopy; Genetic; Genetic Predisposition to Disease; Globulins; Goals; Hour; Human; Hydrolase; Immune system; Immunoglobulin G; Immunoglobulins; In Vitro; Inbred MRL lpr Mice; Inflammation; Kidney; Kidney Diseases; Ligands; Link; Location; Lupus; Lysosomes; Milk; Modeling; Molecular; Mucins; Mus; Pathology; Pathway interactions; Phagocytosis; Process; Production; Receptor Signaling; Recycling; Relative (related person); Role; Serum; Signal Transduction; Surface; Systemic Lupus Erythematosus; T-Lymphocyte; TLR3 gene; TLR7 gene; Testing; Time; Tissues; Toll-like receptors; base; cell motility; chemokine; cytokine; in vivo; late endosome; lupus prone mice; lupus-like; macrophage; prevent; public health relevance; receptor; residence; therapeutic target

DESCRIPTION (provided by applicant): The defective clearance of apoptotic cells and the increase in circulating immune complexes (ICs) have repeatedly been implicated in heightened cytokine secretion in systemic lupus erythematosus (SLE). Despite evidence of clearance defects, and presumably diminished access of TLR ligands to the endosome, cytokine secretion has been found to result from activated endosomal TLRs. This paradox raised the possibility that a more complicated model involving TLR-dependent and TLR-independent mechanisms regulates cytokine secretion. Our preliminary data show that IgG-ICs (IgG-apop ICs) bound in part via Fc?Rs are elevated 30-fold on the surface of DCs and MFs from autoimmune prone MRL/lpr mice. We show that this accumulation results from a degradation defect that promotes the recycling of internalized Fc?Rs bound IgG-ICs. In vivo and in vitro, the accumulation of ICs heightens BAFF secretion. In this application we will test the central hypothesis that IgG-apop ICs accumulate on DCs and MFs due to defects in targeting or degrading ICs within the endocytic/phagocytic pathway. This leads to pathogenic cytokine production as a consequence of genetic predisposition and chronic TLR and/or Fc?Rs signaling. We propose in aim 1 to identify where in the degradative pathway the progression of ICs is attenuated. In aim 2, we postulate that chronic Fc?Rs signaling results when ICs bound to Fc?Rs remain aggregated during the recycling process, and that chronic TLR signaling results when the IC-loaded Fc?Rs spend prolonged time within these pathways. Lastly, we propose that although genetic predisposition might underlie the defects leading to the recycling of ICs, genetic events might also be required for heightened cytokine secretion. We will separate these putative genetic events by pharmacologically inducing IC recycling in non-autoimmune mice and assessing whether this leads to heightened cytokine production. Overall, this proposal is significant because it identifies that ICs accumulate on DCs and MFs and defines a more intricate mechanism for how TLR-dependent and TLR- independent mechanisms might contribute to elevated levels of lupus-related cytokines.

描述（由申请人提供）：凋亡细胞的清除缺陷和循环免疫复合物（ic）的增加反复与系统性红斑狼疮（SLE）细胞因子分泌增加有关。尽管有证据表明存在清除缺陷，并且TLR配体进入内体的途径可能减少，但已经发现细胞因子分泌是由活化的内体TLR引起的。这一悖论提出了一种可能性，即涉及tlr依赖和tlr独立机制的更复杂的模型调节细胞因子的分泌。我们的初步数据显示，igg - ic （IgG-apop ic）部分通过Fc？自身免疫易感性MRL/lpr小鼠的dc和MFs表面Rs升高30倍。我们表明，这种积累是由降解缺陷引起的，降解缺陷促进了内在化Fc？r结合igg - ic。在体内和体外，ic的积累会增加BAFF的分泌。在这个应用中，我们将验证IgG-apop ic在dc和mf上的积累是由于在内吞/吞噬途径中靶向或降解ic的缺陷。这导致致病细胞因子的产生，作为遗传易感性和慢性TLR和/或Fc？Rs信号。我们在目标1中提出确定在降解途径中ic的进展被衰减的位置。在目标2中，我们假设慢性Fc？当ic绑定到Fc时，Rs信令结果？r在循环过程中保持聚合，并且当ic负载的Fc？Rs在这些通路中停留的时间较长。最后，我们提出，尽管遗传易感性可能是导致ic循环的缺陷的基础，遗传事件也可能是细胞因子分泌增加所必需的。我们将通过在非自身免疫小鼠中药理学诱导IC循环来分离这些假定的遗传事件，并评估这是否会导致细胞因子产生增加。总的来说，这一建议意义重大，因为它确定了ic在dc和mf上的积累，并定义了TLR依赖性和TLR非依赖性机制如何促进狼疮相关细胞因子水平升高的更复杂的机制。